Last spring NIH scientist Charles Natanson published a meta-analysis of studies on hemoglobin-based blood substitutes in the Journal of the American Medical Association (Natanson, C., Kern, S. J., Lurie, P., Banks, S. M. & Wolfe, S. M. J. Am. Med. Assoc. 299, 2304-2312 (2008)). Blood substitutes are . . . well . . . blood substitutes. Like blood, they carry oxygen, but have long shelf lives, don’t need refrigeration, don’t require cross-matching and meet the need for situations where there is a shortage of fresh whole blood. A meta-analysis is a systematic summary, often expressed quantitatively, of existing literature. Data from 16 trials of five different blood substitute products were combined. The bottom line of the Natanson analysis?

Overall, there was a statistically significant increase in the risk of death (164 deaths in the HBBS-treated groups and 123 deaths in the control groups; relative risk [RR], 1.30; 95% confidence interval [CI], 1.05-1.61) and risk of MI (59 MIs in the HBBS-treated groups and 16 MIs in the control groups; RR, 2.71; 95% CI, 1.67-4.40) with these HBBSs. Subgroup analysis of these trials indicated the increased risk was not restricted to a particular HBBS or clinical indication.

Conclusion: Based on the available data, use of HBBSs is associated with a significantly increased risk of death and MI. (Natanson et al., JAMA)

Well, not quite the bottom line. One of the product manufacturers, Biopure (Cambridge, MA) demanded he retract the paper, which he declined to do. So Biopure is suing Natanson for “false and defamatory statements,” citing letters he sent to officials in the UK, Greece and South Africa, but also the JAMA publication itself, claiming the paper was so methodologically flawed it could not support his contention Hemopure was a risky product.

The US is known as a litigious society so you may think that lawsuits like this happen all the time. In fact they practically never happen:

Such lawsuits are highly unusual, says Jann Ingmire, director of media relations at JAMA. In 2000, Immune Response of Carlsbad, California, sued authors of a paper published by the journal that presented data showing that the company’s therapeutic HIV vaccine had failed in clinical trials. Immune Response said the authors refused to include additional data that the company felt was favorable towards the vaccine, but later dropped the lawsuit.

Biopure’s case is unlikely to succeed, says patent litigator Steve Keane in the San Diego office of the international law firm Morrison & Foerster. If a judge were to rule in Biopure’s favour with respect to the JAMA article, Keane says, “it would be an unprecedented restraint on scientific speech.” (Heidi Ledford, Nature)

But succeeding in the lawsuit is probably not the objective. Instead Biopure wants to make it expensive and unpleasant for scientists to publish papers critical of biotech and Big Pharma products, in essence, making them think twice before touching the hot stove. Biopure is the kind of company that gives the industry a bad name.

Intimidation via law suits has protected personality test owners for quite some time — we were warned about publishing negative critiques by our grad school profs, because the test publishers would go after us. So the field is littered with utterly useless scales (actuality, damaging scales . . .) that have little or no validity but are making tons of money.

In the case of psych tests, the publisher has an added advantage in court because the statistical and validity issues are complex, so the court focuses on ‘were there/could there be any damages’ resulting from the critical paper. Well, yes . . . less use of an invalid test is an intended outcome — which would decrease income for the publisher. “Damages!” screams the litigant’s attorney, and the judge sagely nods in agreement. So the court decides that all will be well if the critical reviewer pays the publisher. A travesty of judgment, but quite in keeping with the level of legal understanding of validity.

I find minimal solace in the fact that an invalid psych test rarely kills. Medicine requires a much higher standard.

Shall we not mention that the meta analysis actually was flawed because the studies included in the analysis were of non-homogeneous products, some of which were from companies that have been out business for years? Shall we not mention that finding that “Subgroup analysis of these trials indicated the increased risk was not restricted to a particular HBBS or clinical indication.” is by no means a statement which can be used to identify Biopure’s product with an increased risk?

Most importantly, shall we not mention that Natanson’s only patent EVER was for a product that he claimed would reduce the risk associated with Biopure’s product… if only Biopure would concede to the existence of the risk and (presumably) purchase a license to use Natanson’s patent?

Shall we not mention that, although this was Natanson’s only patent, somehow he FORGOT to disclose this to JAMA prior to publishing the article?… which was released only hours prior to Biopure’s meeting with the FDA’s BPAC.

I believe the system is being abused my friends, but not by Biopure. Instead it looks like some kind some kind of an extortion scam that Natanson was playing under the cover of the NIH is about to get exposed. Natanson has already made the NIH and JAMA look like fools.

james: Shall we not mention that using the libel system to make scientific points has consequences, is inappropriate and by your own standards defamatory? Give me a fucking break! NIH and JAMA only look like fools in your eyes or Biopure’s (assuming you have no undisclosed relationships to Biopure of your own; I have none to JAMA, NIH or Natanson, although I acknowledge being a scientist who publishes in the peer reviewed literature and a potential patient who relies on science to keep me safe from harmful products hawked by those more interested in profits than my health).

hmm.
revere’s attitude to conflict of interests seems very interesting. In this case, Natanson disclosed a conflict of interest after publishing this paper. James makes the case that Natanson has a direct financial conflict of interest, and revere just isn’t interested.

revere also took a severe view of conflicts of interest recently, in the case of an MSU professor. Even though he had declared the interest, and had no personal financial interest, it was a foul stench. Revere’s disapprobation was thundering, and highly critical of the FDA. Well, it was, until the professor’s opinion on the BPA analysis turned out to be what revere wanted to hear, and we haven’t heard a squeak out of revere since.

seems conflict of interest only matters when you say something revere disagrees with.

Kind of makes you wonder whether revere has any self-interest in many of the things he discusses on this blog. Clearly since revere is always right, the self-interest won’t matter.

per: No a conflict is a conflict. It doesn’t matter which side. I’m a journal editor and have had to deal with this problem with my authors. On one occasion we forced a correction because of failure to disclose, even though it made no difference. If you read my post, on the MSU case it should have been clear exactly what my problem was. He had a severe conflict, regardless of what the outcome of the panel was. I said it then and I’m saying it now. The FDA should never have had him chair that panel.

Regarding this blog, I have been pretty up front about disclosures. I also rarely write about my own work and when I do I disclose it. But now that you are discussing it per, do you have any disclosures you’d care to make? You seem to have some pretty strong views on the BPA issue. Do you work, for example, on BPA and PPARgamma? If so let’s hear what you have to say.

no offence, revere, but I see a marked contrast in the tone of your articles before the FDA panel opined, when it was all about a foul stench at the FDA, and your articles after the FDA panel opined. They agreed with your view, and you have supported their viewpoint, and have not complained that there viewpoint is untenable because of conflict of interest. It is an open question as to what would have happened if they had come up with a viewpoint that you did not support; would you have then complained about conflict of interest ?

I am not sure about the MSU professor; as I understand it, he told the FDA, he did not personally benefit, and I am not clear that he even indirectly benefits. MSU benefits, clearly. However, if you have more information about who did, or didn’t, benefit, or can correct me, I welcome clarification.

However, if you are setting a standard where you are conflicted out of an issue if someone (who has views on an issue) gives money to your university, that seems to me to be unrealistic, and would conflict out almost all academics from all decision making. So I am not clear what your position is.

I am surprised that you take such a lax view on Natanson’s improper declaration of interest, especially since james made a case that Natanson’s interest may give rise to a conflict of interest.

And as regards your position on conflict of interest, you have made clear that you run 10s of millions of dollars of research funding. All that funding makes for a large area for conflict of interest, and i haven’t seen you disclosing any conflict of interest yet.

And just for the record, it is you who has made the case that conflict of interest is such a big issue, and you who should be addressing this issue impartially.

per: I think I was quite clear in the post. The conflict is not that the MSU prof’s university got money. It is that the Institute he directs got the money, and not a small amount, either. That is a clear conflict. There is also context, here. The FDA (which has not come out on “my side” regarding BPA; they are re-evaluating it after being criticized on every side [except by the BPA industry folks] for faulty science. This includes the panel, that whatever its outcome (in this case agreeing with others who said the science was faulty) had at least the apperance of conflict of interest. I said so previously and I’ll say it again. That’s a serious lapse on the part of the FDA, whatever the out come of that panel.

As regards my own conflict, let me admit to a bias. I am biased in favor of public health. One can have all sorts of bias, including bias in favor of economic competitiveness for certain industries, bias in favor of the fee market, bias in favor of regulation, etc., etc. My bias is in favor of public health. Regarding money, I have no conflicts. I direct a large research program that has labs that do PPAR work, among other things, but no BPA work. I have no personal financial interest, although I do have 3 grandchildren and have the usual concerns for their welfare. My research money comes from NIH.

Now how about you? I asked you what your great interest in BPA was, but you didn’t answer. Are you a scientist working on this or a related area? Do you work for or benefit from the BPA issue in any way? I don’t, other than the ways I have described. I was unaware of the Natanson conflict and believe it should have been disclosed. But the post wasn’t about conflict, it was about using the libel law. It is perfectly reasonable to complain about Natanson’s conflict if he didn’t disclose it. It is not perfectly reasonable to sue him for libel. That has consequences for all of science. It is the wrong and harmful remedy. But that’s another topic.